It is estimated that nucleosides interact with roughly one third of the protein classes in the human genome, including polymerases, kinases, reductases, motor proteins, and structural proteins (Venter et al., Science 291: 1304-1351 (2001)). In addition, nucleosides play a central role in cell metabolism (FIG. 1).
The binding motifs of these nucleosides are associated with a broad array of targets of therapeutic importance in biological systems. The introduction of diverse moieties into the carbohydrate and/or the base subunits of nucleosides is a promising strategy for the identification of specific receptor ligands, enzyme inhibitors and nucleoside function modifiers. Naturally occurring nucleoside analogs demonstrate selective activities such as protein synthesis inhibition (puromycin), glycosyl transferase inhibition (tunicamycin) and methyltransferase inhibition (sinefungin) (FIG. 2). Synthetic nucleoside analogs are known to be therapeutically useful as antipsychotics, cardiotonics, diuretics, analgesic, anti-inflammatory agents, anticonvulsants, antihypertensives, antibiotics, antivirals, and anticancer agents (FIG. 3). Many of these nucleoside analogs are either on the market or in advanced clinical stages.
The increasing resistance of pathogens, the often severe side effects of nucleosides in chemotherapy and the lack of selective ligands for adenosine receptor subclasses despite extensive medicinal chemistry research emphasizes the need for nucleoside analogs in high number and diversity. The availability of high throughput screening capabilities together with the combinatorial synthesis of small organic molecule libraries offers a unique opportunity to accelerate the discovery of novel pharmaceutical targets and leads, especially with biologically privileged scaffolds like nucleosides in hand.
It is known that extracellular purines (e.g. adenosine, ADP and ATP) and pyrimidines (e.g. UDP and UTP) mediate diverse biological effects via cell-surface receptors termed purine receptors. Their complex and multifunctional role in modulating cellular and tissue function can be conceptualized as a purinergic cascade. Agonists of purine receptors with increased stability and selectivity may be achieved by synthesizing analogs of natural nucleosides. Analogs can be produced by modifications to the nitrogenous base rings and the 5′ position of the nucleoside moiety.
Thus, there is a need in the art for efficient and rapid methods for synthesizing nucleoside analogs. While solid phase oligonucleotide synthesis is well established, there remains a need for more efficient methods for solid phase synthesis of nucleoside analogs. The present invention fulfills these and other needs.